title: A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome.
abstract: The transforming growth factor β (TGF-β) family of growth factors are key regulators of mammalian development and their dysregulation is implicated in human disease, notably, heritable vasculopathies including Marfan (MFS, OMIM #154700) and Loeys-Dietz syndromes (LDS, OMIM #609192). We described a syndrome presenting at birth with distal arthrogryposis, hypotonia, bifid uvula, a failure of normal post-natal muscle development but no evidence of vascular disease; some of these features overlap with MFS and LDS. A de novo mutation in TGFB3 was identified by exome sequencing. Several lines of evidence indicate the mutation is hypomorphic suggesting that decreased TGF-β signaling from a loss of TGFB3 activity is likely responsible for the clinical phenotype. This is the first example of a mutation in the coding portion of TGFB3 implicated in a clinical syndrome suggesting TGFB3 is essential for both human palatogenesis and normal muscle growth.
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA 94070, USA. hrienhoff@datahooks.com
authors.forename: Hugh Young
authors.initials: HY
authors.lastname: Rienhoff
authors.forename: Chang-Yeol
authors.initials: CY
authors.lastname: Yeo
authors.forename: Rachel
authors.initials: R
authors.lastname: Morissette
authors.forename: Irina
authors.initials: I
authors.lastname: Khrebtukova
authors.forename: Jonathan
authors.initials: J
authors.lastname: Melnick
authors.forename: Shujun
authors.initials: S
authors.lastname: Luo
authors.forename: Nan
authors.initials: N
authors.lastname: Leng
authors.forename: Yeon-Jin
authors.initials: YJ
authors.lastname: Kim
authors.forename: Gary
authors.initials: G
authors.lastname: Schroth
authors.forename: John
authors.initials: J
authors.lastname: Westwick
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Nazli
authors.initials: N
authors.lastname: McDonnell
authors.forename: Judith G
authors.initials: JG
authors.lastname: Hall
authors.forename: Malcolm
authors.initials: M
authors.lastname: Whitman
mesh_terms: D000328:Adult; D000818:Animals; D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D006130:Growth Disorders / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D055947:Loeys-Dietz Syndrome / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis / Q000235:genetics*; D018908:Muscle Weakness / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D015398:Signal Transduction; D053782:Transforming Growth Factor beta3 / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis / Q000378:metabolism
chemical_list: C509044:TGFB3 protein, human; D053782:Transforming Growth Factor beta3
keywords: Loeys-Dietz syndrome; Marfan syndrome; bifid uvula; de novo mutation; distal arthrogryposis; exome sequencing; hyomyoplasia; low muscle mass; transforming growth factor beta